A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen

Abstract

Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest inherited cause of retinal detachment and one of the commonest autosomal dominant connective tissue dysplasias. There is clinical and locus heterogeneity with about two thirds of families linked to the gene encoding type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have a characteristic congenital vitreous anomaly and are linked without recombination to markers at the COL2A1 locus. In contrast families with the type 2 variety have a different vitreo-retinal phenotype and are not linked to the COL2A1 gene. Type XI collagen is a quantitatively minor fibrillar collagen related to type V collagen and associated with the more abundant type II collagen fibrils. A mutation in COL11A2, the gene for alpha 2 (XI) procollagen, has recently been found in a family described as having Stickler syndrome, although there was no ocular involvement. Here we show for the first time that a family with the full Type 2 Stickler syndrome including vitreous and retinal abnormalities is linked to the COL11A1 gene and characterise the mutation as a Glycine to Valine substitution at position 97 of the triple helical domain caused by a single base G-->T mutation. These results are the first to provide confirmation that type XI collagen is an important structural component of human vitreous. They also support previous work suggesting that mutations in the genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, but of these, only mutations in COL11A1 will give the full syndrome including the vitreo-retinal features.

Molecular genetics of rhegmatogenous retinal detachment

“…Using rarer (type 2) families, which lacked the membraneous anomaly, linkage of one family to COL11A1, the gene for ␣1(XI) collagen was demonstrated and the first mutation (Gly97Val) in this gene characterised. 19 Analysis of two other families found an exon skipping mutation and a large multiexon deletion in COL11A1. 20 All three of these families had a vitreous with a beaded appearance to its structure (Figure 2).…”

Evaluation and management of pediatric rhegmatogenous retinal detachment

“…24,25 Type II Sticker syndrome is characterized by a beaded condensation in the retrolenticular space and is associated with dominant mutations in the COL11A1 gene, which encodes for collagen type XI. 20,[26][27][28] Marshall syndrome includes the findings of ''ectodermal dysplasia,'' hearing defects, a flat nasal bridge, and ocular abnormalities that include myopia, clear vitreous gel, and congenital cataract. It is also associated with autosomal dominant mutations in the COL11A1, indicating that they are overlapping genetic syndromes.…”

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

“…Mutations in COL1A1 and COL1A2 are responsible for osteogenesis imperfecta (Pope et al, 1985;Pihlajaniemi et al, 1984) and COL1A2 is also one of the most highly expressed in the Morton cochlear cDNA library (Skvorak et al, 1999;Resendes et al, 2002). COL4A3 and COL4A5 mutations are associated with Alport syndrome (Lemmink et al, 1994b;Barker et al, 1990), while disruption of COL11A1 and COL11A2 causes Stickler syndrome (Richards et al, 1996;Vikkula et al, 1995). Several modifiers of extracellular matrix, including matrix metallopeptidase 2 (Mmp2), Mmp14 and Mmp15 also share a similar expression pattern.…”